[P1-196] “Metabolic Microcephaly” Due to Abnormal Amino Acid Metabolism: A New Group of Neurodevelopmental Disorders
Microcephaly is an important cause of neurological morbidity in children and genetic causes are common. The underlying mechanisms of genetic microcephaly syndromes are highly diverse, with microcephaly genes being implicated in many biological processes. Through the evaluation of 88 families with undiagnosed microcephaly, we identified mutations of three novel amino acid metabolism genes in nine families. These genes are PYCR2 (4 families), which is involved in proline biosynthesis, GPT2 (2 families), which catalyzes reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and ASNS (3 families), which catalyzes asparagine synthesis. Affected individuals shared a common radiological feature of cerebral white matter abnormalities, but their metabolic screening tests including amino acid profiles in blood and/or cerebrospinal fluid were negative. We applied clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing to create cellular models of these microcephaly syndromes. PYCR2-deficient cell lines and GPT2-deficient cell lines generated by CRISPR-Cas9 genome editing showed increased apoptosis under oxidative stress. Cell lines deficient in ASNS showed reduced viability due to cell cycle defects and increased apoptosis. These deficiencies were successfully rescued by asparagine supplementation of the culture medium. Our findings suggest that this unique subgroup of microcephaly syndromes (“metabolic microcephaly”), characterized by mutations in genes involved in amino acid metabolism and negative clinical biochemical testing, could be common among undiagnosed neurodevelopmental disorders with microcephaly.